EP300 facilitates human trophoblast stem cell differentiation

生物 滋养层 细胞滋养层 胎盘形成 细胞分化 细胞生物学 癌症研究 遗传学 胎盘 胎儿 基因 怀孕
作者
A. Jantine van Voorden,Remco Keijser,Geertruda J. M. Veenboer,Solange A. Lopes Cardozo,Dina Diek,Jennifer A. Vlaardingerbroek,Marie van Dijk,Carrie Ris‐Stalpers,Ans M. M. van Pelt,Gijs Afink
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [National Academy of Sciences]
卷期号:120 (28) 被引量:12
标识
DOI:10.1073/pnas.2217405120
摘要

Early placenta development involves cytotrophoblast differentiation into extravillous trophoblast (EVT) and syncytiotrophoblast (STB). Defective trophoblast development and function may result in severe pregnancy complications, including fetal growth restriction and pre-eclampsia. The incidence of these complications is increased in pregnancies of fetuses affected by Rubinstein–Taybi syndrome, a developmental disorder predominantly caused by heterozygous mutations in CREB-binding protein ( CREBBP ) or E1A-binding protein p300 ( EP300 ). Although the acetyltransferases CREBBP and EP300 are paralogs with many overlapping functions, the increased incidence of pregnancy complications is specific for EP300 mutations. We hypothesized that these complications have their origin in early placentation and that EP300 is involved in that process. Therefore, we investigated the role of EP300 and CREBBP in trophoblast differentiation, using human trophoblast stem cells (TSCs) and trophoblast organoids. We found that pharmacological CREBBP/EP300 inhibition blocks differentiation of TSCs into both EVT and STB lineages, and results in an expansion of TSC-like cells under differentiation-inducing conditions. Specific targeting by RNA interference or CRISPR/Cas9-mediated mutagenesis demonstrated that knockdown of EP300 but not CREBBP, inhibits trophoblast differentiation, consistent with the complications seen in Rubinstein–Taybi syndrome pregnancies. By transcriptome sequencing, we identified transforming growth factor alpha (TGFA, encoding TGF-α) as being strongly upregulated upon EP300 knockdown. Moreover, supplementing differentiation medium with TGF-α, which is a ligand for the epidermal growth factor receptor (EGFR), likewise affected trophoblast differentiation and resulted in increased TSC-like cell proliferation. These findings suggest that EP300 facilitates trophoblast differentiation by interfering with at least EGFR signaling, pointing towards a crucial role for EP300 in early human placentation.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
余鱼完成签到,获得积分10
3秒前
Orange应助joe_liu采纳,获得10
3秒前
3秒前
田様应助健壮的紫菱采纳,获得10
4秒前
Zhangtao完成签到,获得积分10
4秒前
4秒前
压缩机发布了新的文献求助200
4秒前
香蕉觅云应助Hunter采纳,获得10
4秒前
dyzssg完成签到 ,获得积分10
5秒前
多多完成签到,获得积分10
6秒前
科研谢啦发布了新的文献求助10
6秒前
8秒前
9秒前
lin应助111采纳,获得50
12秒前
彼方发布了新的文献求助10
13秒前
bkagyin应助zoe采纳,获得10
13秒前
科研谢啦完成签到,获得积分10
14秒前
靓丽傲玉发布了新的文献求助10
15秒前
15秒前
中旬日发布了新的文献求助10
16秒前
17秒前
Daily完成签到,获得积分10
17秒前
18秒前
20秒前
actor2006完成签到,获得积分10
21秒前
科研通AI2S应助科研通管家采纳,获得10
22秒前
CodeCraft应助科研通管家采纳,获得10
22秒前
无花果应助科研通管家采纳,获得10
22秒前
Hello应助科研通管家采纳,获得10
22秒前
今后应助科研通管家采纳,获得10
22秒前
22秒前
领导范儿应助科研通管家采纳,获得10
22秒前
22秒前
24秒前
烟花应助七月采纳,获得10
24秒前
靓丽傲玉完成签到,获得积分10
25秒前
科研通AI5应助王道远采纳,获得100
25秒前
26秒前
Liandong发布了新的文献求助10
26秒前
Yang发布了新的文献求助10
27秒前
高分求助中
Les Mantodea de Guyane Insecta, Polyneoptera 2500
Mobilization, center-periphery structures and nation-building 600
Technologies supporting mass customization of apparel: A pilot project 450
China—Art—Modernity: A Critical Introduction to Chinese Visual Expression from the Beginning of the Twentieth Century to the Present Day 430
Tip60 complex regulates eggshell formation and oviposition in the white-backed planthopper, providing effective targets for pest control 400
A Field Guide to the Amphibians and Reptiles of Madagascar - Frank Glaw and Miguel Vences - 3rd Edition 400
China Gadabouts: New Frontiers of Humanitarian Nursing, 1941–51 400
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 物理 生物化学 纳米技术 计算机科学 化学工程 内科学 复合材料 物理化学 电极 遗传学 量子力学 基因 冶金 催化作用
热门帖子
关注 科研通微信公众号,转发送积分 3793299
求助须知:如何正确求助?哪些是违规求助? 3338015
关于积分的说明 10288400
捐赠科研通 3054639
什么是DOI,文献DOI怎么找? 1676091
邀请新用户注册赠送积分活动 804095
科研通“疑难数据库(出版商)”最低求助积分说明 761752